The major thrust of the proposed work will be to identify, at the cellular level, mechanisms by which surface and other epithelial cells of the stomach are injured and are repaired in circumstances commonly encountered in daily life. Simultaneously, factors which affect such injuries, both favorably and adversely, will be evaluated. Of special interest are those circumstances which influence cell migration after injury and those which allow or facilitate death of gastric epithelial cells. Finally, since H. pylori infection has such far-reaching implications in terms of benign and malignant disease, the process by which H. pylori infection alters epithelial cells to facilitate cell death and survival will be examined in detail. The investigations will be directed toward the following: a) To further understanding of wound repair after injury with particular reference to the role of intracellular pH, cell volume, and intracellular signaling pathways regulated by Rho, Rac, and Cdc42 in the migration of cultured gastric (surface) epithelial cells. In addition, to define the way in which factors associated with H. pylori infection, such as vacuolating cytotoxin and ammonia, affect restitution (in vitro) and the migration of cultured gastric epithelial cells after injury. b) To define the cytotoxic effects of factors associated with H. pylori infection, such as vacuolating cytotoxin and ammonia, on gastric epithelial cells. Specifically, whether exposure of cultured gastric parietal, chief, or surface cells to these toxins causes severe ATP depletion (by affecting mitochondrial respiration) resulting in either necrotic or apoptotic death. c) To evaluate the expression of cell death and cell survival proteins, such as Fas, Fas Ligand, Bcl-2, and Bax in normal gastric epithelial cells and to determine whether infection with H. pylori modulates the expression of these proteins to result in either accelerated cell death or prolonged cell survival.